Abstract P196: Chemerin Activates Procontractile Pathways in Isolated Arteries

Abstract

In the vasculature, the adipokine chemerin is present in perivascular adipose tissue and causes arterial contraction through activation of the heptahelical receptor ChemR23. We presently test the hypothesis that ChemR23 is linked to procontractile signaling pathways in isolated arteries. The isolated, endothelium-denuded thoracic aorta of both male and female rats was used for measurement of isometric contraction and biochemical analyses. The peptide analog chemerin-9 (1 nm -3 μM) caused concentration-dependent contraction in both isolated aorta from male and female, with a maximum of ~80% of a phenylephrine (10 μM) contraction. The L type voltage dependent calcium channel inhibitors verapamil (1 μM) and nifedipine (1 μM), as well as the protein kinase C (PKC) inhibitor chelerythrine chloride (10 μM), abolished chemerin-9 induced contraction relative to vehicle-incubated tissues (male and female). Next most effective in inhibiting chemerin-9-induced contraction were the Rho Kinase inhibitors Y27632 (1 μM) and fasudil (1 μM), both effective in male and female aorta. The p38 MAPK inhibitor SB203850 (10 μM) and phosphoinositide-3-kinase inhibitor LY294002 (10 μM) were significantly less effective in reducing chemerin-9-induced contraction in both sexes, reducing maximum contraction in male and female by less than 50%. Finally, the phospholipase C inhibitor U73122 (5 μM) and Erk MAPK inhibitor PD098059 (1 μM) did not shift or reduce chemerin-9-induced contraction compared to control. Western analyses of chemerin-9-contracted tissues validated activation of phosphoinositide-3-kinase and lack of activation of the Erk MAPKs. These data are the first to associate ChemR23 with L type channel and Rho Kinase activation, and support the hypothesis that ChemR23 taps into some but not all of the well-recognized contractile pathways. This is important knowledge for understanding the mechanisms by which chemerin could support obesity-associated hypertension